[ Please welcome our guest blogger, who identifies as robin, just your average everyday neuropharmacologist. -DM ]
One of the most important yet overlooked tasks of the average pharmacologist is dissolving drugs into solution. Those of you who work with things that don't have to cross the blood-brain barrier probably have a generally easier time dissolving shit than those of us who prefer to study CNS-active compounds. For those of us who play with compounds that are hydrophobic enough to cross the blood-brain barrier, I can testify that those range from fairly easy to major suck to put into an aqueous solution.

The principal reason this is important is pharmacokinetics. I almost said simple pharmacokinetics, but those two words really only belong together when the intent is sarcastic. In the in vivo model, one has to contend with the processes of absorption and distribution before the drug can go to work. Absorption, being the first step, is crucial.
In order for a drug to do its thing, it first has to be absorbed into the bloodstream. A typical experimental route of administration is through the peritoneal cavity, or i.p. This is not injecting directly into the bloodstream, but there is quite a bit of blood circulating in the general vicinity. The drug has to pass through all of the membranes standing between it and the blood in order to begin to circulate to its site of action. And once we've got this batch of drug molecules running around in the bloodstream, presuming they got there in the first place? They're hanging out in the fat cells, or not. They're slowly (or quickly) making their way to the site of action. And that's not even considering the metabolism and excretion parts of pharmacokinetics! You see there are many variables to in vivo pharmacology, even under the most optimal conditions.
So what happens when things go wrong? Say the drug is not dissolved. It's decided it hates you (ok, probably too much anthropomorphizing, but at this point I might as well go for it) and when you add anything the least bit aqueous, it crashes out of solution into crystallized form. Convenient way to isolate a drug, perhaps- shitty way to prepare one for use. If this happens and you try to gather some of this shit up and inject anyway, well, you're doin it wrong. The drug needs to be in some kind of homogeneous solution.
Why do we care? Pharmacologists like to see a drug concentration-response effect when looking for drug effects. Drug concentration is a measure of how much drug is dissolved in solution. Using an incompletely dissolved drug will not reflect the drug concentration, but instead how many crystals comprised of how many milligrams (or fractions thereof) that you randomly collected for that particular syringe draw- if you collected any at all. Dissociation of molecules from the crystallized form into the body compartment is a major rate-limiting step in absorption. This is a crucial step in the oral dosage format, but injection of solutions is intended to bypass some of the common problems of oral dosing. In this case, the intended, effective drug concentration might never be reached.
But there are more reasons than just the theoretical science here. The crystal might not fit through an appropriately sized needle, for one. And pushing a crystallized drug can cause undue pain to the subject, which is to be avoided at all costs. These are not secondary concerns; they are non-negotiable from an ethical standpoint.
So what do you do? There are ways around it- rain dances that we do. Some dissolve hydrophobic drugs straight up in some kind of oil and inject as an oil depot. This is a slower pharmacokinetic situation, because the drug equilibrating between the oil and the body is a huge rate-limiting step. Hydrophobic interactions between drug molecules can slow absorption considerably. But it's useful for some types of studies. In general, aqueous solution is preferred. Why? Most simply, we want the drug solution to be miscible with the aqueous body compartment that receives the injection. But we don't like to add pure water into biological systems. Pure water screws with the delicate ionic balance maintained by cells, and causes major trouble. Saline is the default water-based injection vehicle. Creating an aqueous solution sometimes requires one to fuck around for ages (in bench-science time) finding the lowest percent of [choose your oil-based substance] that will keep the drug in solution. And in some cases, you can dilute a hydrophobic drug in a non-aqueous solvent far enough that adding aqueous liquid slowly and carefully will not cause it to crash out of solution. It all depends on the drug and the concentration you're looking for, but it's usually a task.
What about emulsions? Consider propofol, a short-acting intravenous anesthetic and recent headline-maker in the death of Michael Jackson. Propofol is totally fucking hydrophobic. You will not for the life of you get that shit into a water-based solution. In this case, in order to prepare the drug sufficiently for use in people, it is dissolved in oil first. The drug dissolved in oil is mixed with aqueous solution and surfactants, and processed to a uniform oil droplet size and dispersion in the aqueous solution. The surfactants keep the oil droplets suspended in the water-based solution, whereas oil droplets would typically merge and separate from solution without surfactants. The small size of the oil droplets increases drug surface area, improving drug-blood equilibration time. (note that i.v. means the drug goes straight into the bloodstream.) This is the next-best thing because the amount of drug is evenly distributed through the solution. If it was not properly distributed, physicians would not know whether they were giving a proper dose to maintain sedation and anesthesia. With any drug concentration unknown or outside a certain error margin, major problems arise. With propofol, patients might wake up during surgery without sufficient drug administration- or conversely, they might overdose with too much. Both are very much undesirable, and this potential source of error is considerably reduced due to proper procedure in dissolving drug.
While we experimental pharmacologists may work in very different settings and conditions than, say, your average anesthesiologist- the principles of drug dissolution remain the same. In order for the drug to work for us, we have to work with the drug to get it into solution. Taking the time and trouble to do it right matters.

Whenever something does not dissolve in water, the first thing I try is DMSO. Very frequently a concentrated stock in DMSO can be diluted ~10X into a little bit of detergent. Also, what about simply rubbing the solution in DMSO into the skin? Is DMSO used much in neuropharmacology?

First of all, many thanks to DM for encouraging me to finish this as a post and for hosting it on the blog.
I think ethanol can be useful, depending on the drug and what you want to look at. Of course, a significant amount of ethanol will confound your drug effect of interest. Whether that is intended, I will leave up to interpretation 🙂
DMSO is a good tool but I try to avoid >5% concentration in final injection solution. Some of the drugs I have worked with have shown interactions with higher percentages of DMSO, but YMMV. It is great at getting things across the skin, but when you work with subjects that are covered in fur, that gets more complicated.
Heat and sonication are common methods to push a drug into solution. Again, your result depends on how your drug behaves. Some will stand up to it, some break down on you when you heat them, etc.
"Depends on your drug" is a phrase I use a lot. That's a common joy and frustration of my work.

Reach for the alpha, beta, or gamma cyclodextrins (depending upon the size of your molecule of interest). Cyclodextrins are the secret behind Febreze. The cyclodextrin is a conical-donut shaped sugar molecule that essentially envelopes your drug molecule (well, stink molecule in the case of Febreze). It often works like magic, and its my best friend when it comes to those pesky indissolvables. Its also pretty well tolerated in IM injections.

Cyclodextrins would work great, but be careful - they may redefine the ADME properties of the drug. The inside of the cyclodextrin molecule is hydrophobic, so a hydrophobic drug, which is supposed to act immediately, may in fact be only slowly released from the complex. Also, the complex will be very unlikely to cross the blood-brain barrier. Actually, this is an interesting subject to study...

My experience working with hydrophobic molecules is not different from that of Robin. However, in a couple of studies, working with such compounds, I sought the help of an organic chemistry colleague who was willing to try a different approach i.e., conjugating the active molecule with a hydrophilic yet, inert compound, which could significantly increase the aquaous solubility of the active drug. In those two cases we had tried, the drugs in question both crossed the BBB and exerted their desirable effects.

Ooh, cyclodextrins. That's an interesting one I hadn't thought of. I think that in the right scenario that might be a great trick- but as Gummibears pointed out, you risk having an effect similar to an oil depot where you're waiting for the drug to pass from the hydrophobic to the hydrophilic compartment. So, back to that damned right-scenario caveat!
I had to investigate nanojackets- thanks for the pointer, becca! I'm interested to see how that will play out.
SR, I admit to having only limited experience playing in the sandbox with organic chemists, but in that limited experience I've found that altering molecular structure can have major effects beyond solubility.

If you want to play with simple organic chemistry, you may want to consider transforming the structure into a more hydrophilic prodrug. For propofol, which you used as an example, phosphorylation of the -OH works great (the phosphate ester is then efficiently enzymatically dephosphorylated in vivo, yielding propofol and the phosphate anion).

Good call on the pro-drug. I have worked with different applications from the organic chem side (loosely, altering sidechain length, functional groups, substitutions, and such) so I was focused on that type of molecular alteration. Thing is, how many good active molecules are amenable to use as a pro-drug? In the propofol example- why don't we administer propofol as a pro-drug? Perhaps because the time to action is significantly longer if we rely on metabolism to create the pharmacologically active drug form for us?